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84.An 18-year-old man who has Duchenne muscular dystrophy with confirmed exons 45-50 deletion has been wheelchair dependent since age 12 years and requires BiPAP ventilation nearly 24 hours a day. History includes cardiomyopathy, multiple pneumonias, scoliosis, osteoporosis, and contractures in the arms and legs. He was treated with glucocorticosteroids from age 9 to 12 years. His parent asks about the efficacy and potential access of eteplirsen for her son. Eteplirsen currently has provisional FDA approval and a restricted patient access program can provide the drug to qualified patients. Which of the following statements is the most appropriate response?

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In 2017, the FDA awarded provisional approval to eteplirsen for Duchenne muscular dystrophy (DMD). DMD is an x-linked dystrophy due to loss of function mutations in the dystrophin gene . Single or multiple exon deletions are the most common cause of DMD and alter the reading frame of the truncated mRNA, resulting in complete loss of dystrophin protein expression.

Thirteen percent of patients who have exon deletions (45–50, 47–50, 48–50, 49–50, 50, 52 or 52–63) are amenable to exon-skipping gene therapy that results in exclusion of exon 51; this causes an in-frame shift deletion that results in formation of a functional yet truncated protein.

Eteplirsen is an antisense morpholino that specifically targets exon 51 and has been shown to restore dystrophin expression in vitro and in vivo. Authors of a phase I/II trial reported safety, tolerability, and successful exon skipping associated with eteplirsen. A larger 48-week, placebo-controlled trial was then initiated in 7- to 13-year-old boys with DMD who could still ambulate. The study confirmed its safety, tolerability, and exon skipping. The authors also presented evidence of increased protein expression in >40% of treated muscle fibers and modest improvement in walking distance in treated patients at end of study, although analysis excluded two subjects who precipitously declined. The FDA initially rejected an application for an accelerated approval given that a clear clinical effect was not observed in the placebo- controlled study and the actual magnitude of dystrophin protein expression was in doubt. Due to pressure from physicians, patients, and advocacy groups, the FDA granted provisional approval pending the results of a large, ongoing phase III clinical trial.

Patients with exon 51−skipping amenable disease await results of the phase III trial but may be able to obtain eteplirsen through an early access program; unfortunately, this program currently is not available in the United States. If the program eventually is approved, challenges remain regarding its projected cost (>300K/year), insurance coverage, and requirements based on clinical disease stage and insurance approval criteria.

References

  • Eteplirsen Drug Access program
  • Dowling JJ. Eteplirsen therapy for Duchenne muscular dystrophy: skipping to the front of the line. Nature Rev Neurol. 2016;12(12):675-676.
  • Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). Neurology. 2017 Apr;88(16 Suppl):S42.001.

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